The phenomenon of polymorphism is generated by the possibility that the same substance organizes in different crystalline forms (polymorphic forms), crystallizes with solvent molecules (hydrates and solvates) or solidifies without periodicity (amorphous substances).
The different crystalline or amorphous phases, even if of the same substance, can have different chemical, physical and mechanical properties and in case of active drug substances different characteristics of bioavailability and therapeutic efficiency. Furthermore, the same product in different crystalline or amorphous phases may present different characteristics of chemical stability.
Regadenoson (compound identified by Registry Number: 313348-27-5) was described for the first time in WO00/078779 and has the following structural formula

This compound is an A2A adenosine receptor agonist responsible for regulating myocardial blood flow by vasodilating the coronary arteries and increasing blood flow to the myocardium. Regadenoson is employed as heart imaging aids where, prior to administration of an imaging agent, coronary arteries are dilated and then, by observation of the images thus produced, the diagnosis of a possible coronary artery disease (CAD) can be performed.
This compound is described to have different polymorphic forms identified as polymorphic forms A, B, C and D as well as an amorphous form.
The stability of these solid states is critical in order to allow the synthesis of this compound on a preparative scale. It is known by literature data that polymorphic form A, disclosed in U.S. Pat. No. 8,106,183, and D, disclosed in WO2012149196 are the more stable polymorphic forms and are the preferred solid states in which Regadenoson can be isolated and used for formulative purposes.
More in detail, polymorphic forms A, B, C and an amorphous form were disclosed in U.S. Pat. No. 8,106,183. In this patent, the crystalline forms are defined by means of X-Ray diffraction spectroscopy (XRD spectroscopy), differential scanning calorimetry data (DSC); the methods of preparation were also given.
Regadenoson polymorphic form A was identified as a monohydrate form; this form may be produced by crystallization of Regadenoson from protic solvents (for example ethanol or ethanol/water mixtures) or from a polar solvent (for example dimethylsulfoxide/water). Regadenoson Form A was identified by the authors of U.S. Pat. No. 8,106,183 as more stable than polymorphs B and C at ambient temperature and also under relative humidity stress conditions up to its melting point (identified by DSC as 194.5° C.).
Polymorphic forms B, C and the amorphous form were described as solid states, which could not easily prepared and/or proving unstable. Form B is prepared by evaporating under vacuum a solution of Regadenoson in trifluoroethanol at ambient temperature. However, its constitution could not be determined by the inventors of U.S. Pat. No. 8,106,183 because of X-ray disordered broad peaks, the polymorph contained variable amounts of water and its reliable preparation could not be reproduced. Polymorph C was prepared by slurrying Regadenoson in acetonitrile at 60° C. for a long period of time. This polymorph showed a distinct X-ray spectrum, but showed to be a variable hydrate, unstable at high temperatures.
In U.S. Pat. No. 8,106,183 the method of preparation of an amorphous form of Regadenoson is described by heating polymorphic form A at 200° C.; this solid state, differently by polymorphic forms A-C, was not described by the authors by an X-ray diffraction spectrum in order to identify possible characteristic halo-peaks (broad peaks). This amorphous form was prepared according to U.S. Pat. No. 8,106,183 by heating the polymorphic form A over the melting point value of this substance (that for polymorphic form A is 194.5° C.). This method is not industrially applicable and leads to the formation of several side products. The present inventors have found that this thermal treatment causes a decrease of chromatographic purity of about 30% and a change in the color of the sample (Regadenoson polymorphic form A is a white substance but after a thermal treatment at 190-200° C. the color changes to brown). To the best of our knowledge, this is the only described method for the preparation of amorphous Regadenoson.
Form D is disclosed in WO2012149196 as stable under inert conditions. This form contains between 0.8 and 1.7% by weight of water hydration and is indicated as useful for the preparation of solutions for administration, such as parenteral solutions. Form D is prepared through a complete new synthesis of Regadenoson, also disclosed in this reference. Regadenoson HPLC fractions of purity >99% are combined and concentrated to a paste. The supernatant is decanted and the flask is heated in an oil bath at 150° C. under reduced pressure of 20 mmHg for 6 hours to give Form D.
These literature data indicate that only the polymorphic forms A and D were identified as stable compounds, however, some precautions must be taken for their storage conditions and handling.
There is a strong need in the pharmaceutical industry for the preparation of stable solid forms of Regadenoson in an industrially easy and convenient manner. There is also the need for an easy and convenient process to convert the amorphous form into more thermodynamically stable polymorphic forms.
Moreover, there is also a strong need to have available solid forms of Regadenoson which are stable also in normal atmospheric conditions, in particular in humid conditions, without the need to store them in controlled atmospheric or inert conditions, with evident advantages in terms of handling and costs.
The present invention overcomes the technical problem of stability of polymorphic forms of Regadenoson by providing a process for the preparation of Regadenoson amorphous form and its conversion into new stable solid forms.